Tauopathies, a heterogeneous group of neurodegenerative diseases, feature insoluble deposits of the microtubule-associated protein tau. A causal role for tau misfolding in disease is supported by the fact that multiple mutations associated with an increased propensity for aggregation cause autosomally dominant forms of the disease. Previous work from our lab as well as from others' suggests that the tau protein can propagate misfolding from the outside to the inside of the cell, and between cells in a prion-like fashion. This mechanistic paradigm is also implicated in other disorders including synucleinopathies, polyglutamine expansion diseases, and frontotemporal dementia/ALS spectrum diseases. However, whether or not the proteins associated with these diverse diseases are true prions, defined by the ability to propagate unique conformations, is an unsettled matter. Preliminary data suggests that exogenous tau fibrils induce the misfolding of endogenously expressed tau repeat domain (RD, aa 244-372), which stably propagates its amyloid state to daughter cells as biochemically distinct prion strains. These conformations can be isolated from cells and re-introduced into nave cells to seed self-propagating aggregates with the same phenotypic characteristics. Brain homogenates from human patients with different tauopathies induce the formation of unique tau aggregate strains. Building on preliminary data, the present work addresses two hypotheses: 1) Distinct strains are associated with distinct tauopathies; 2) There is a direct correlation between a strain's conformational stability and its ability to seed further aggregation and induce toxicity. If successful, this work will provide compelling evidence for tauopathies having a prion etiology and will gather mechanistic insight into the factors that dictate strain formation, strength, and toxicity. This research is significan because it could help lead to more accurate diagnosis of tauopathies, and to more precise antibody-based treatments that target extracellular protein, which are gaining increasing attention as potential therapies